Many of the most important and clinically relevant aspects of mental function involve the same biochemical processes that underlie synaptic plasticity. In contrast to the many electrophysiological studies addressing mechanisms underlying synaptic plasticity, only limited information is available on the anatomy of this plasticity. The proposed research addresses the pre- and postsynaptic structural basis of synaptic plasticity in forebrain. Specific Aim 1a will determine whether soluble guanylyl cyclase (sGC, a principal receptor for nitric oxide) concentrates selectively in axonal terminals presynaptic to nitric oxide synthase-positive postsynaptic densities in cerebral cortex. Specific Aim 1b will examine the anatomical organization of two downstream targets of nitric oxide, PKG and cyclic nucleotide-gated channels, to determine whether they are preferentially found in axonal terminals also enriched in sGC. To define the anatomical substrate underlying glutamate receptor trafficking, Specific Aim 2A will characterize ultrastructural aspects of ligand-induced AMPA receptor endocytosis in primary neuronal cultures. Specific Aim 2B will characterize the organization of PICK1, a protein implicated in receptor trafficking, determining whether treatments that trigger AMPA receptor endocytosis may change the distribution of this molecule in the vicinity of the postsynaptic density, in intact brain.